It has long been recognized that natural selection and evolution build complexity into natural proteins and biological systems [1-3]. This complexity frustrates biochemists seeking to understand structure and function [4], and presents an extraordinary challenge to protein engineers who aim to reproduce or create new functions in proteins. So far, this complexity has severely constrained the ability of protein engineers to approach the efficiency of natural protein catalysts [5-10]. No matter how common it may be in nature, complexity may in fact not be an essential feature of the proteins per se, nor may it be in fact an essential feature of catalysis, as shown by synthetic chemical systems [1,1]. By understanding the origins of complexity and attempting to separate multiple utilities and minimize complexity during the design and testing of artificial proteins that are completely independent of natural selection, it may be feasible to progressively build in sophisticated biochemical features that reproduce and exceed natural protein function.
Protein function requires more than a static structure [1,2]. In natural proteins, the motion that is part of engineering of protein function is often specific, which can make re-engineering motion for new functions prohibitively difficult. In contrast, artificial proteins offer a full palette of motions that can be edited to facilitate those that are productive and remove those that are unproductive.
Research efforts around protein design and engineering are driven by the great need to identify artificial proteins that are able to carry out functions once thought to be exclusive to naturally occurring proteins. Central targets in protein engineering are hemoglobin and related globins that are in charge of transporting molecular oxygen in the body. An artificial protein capable of performing hemoglobin's role in gas transport would find applications in boosting the blood's ability to carry oxygen gas and replacing depleted hemoglobin and/or red blood cells in patients. The present invention addresses this long-standing need.